18 - Haematology Principles Flashcards
What will tests show if there is haemolytic anaemia?
- Low Hb
- High bilirubin
- Reticulocytosis
- Raised LDH
- Raised urinary urobilinogen
What are the different classifications of haemolytic anaemia and give some examples of each?
- *• Hereditary** v Acquired
- *• Immune** (Coombs +ve) v Non-immune (Coombs -ve)
- *• Extravascular** v Intravascular
What can inherited haemolytic anaemias be classified by?
- Erythrocyte membrane
- Haemoglobin molecule e.g sickle cell, thalassemia
- Metabolic disturbance e.g G6PD deficiency
What can acquired haemolytic anaemias be classified by?
Immune Mediated
- Haemolytic transfusion reactions
- Haemolytic disease of the newborn
- Cold and Warm AIHA
Non-immune mediated
- Mechanical trauma - due to heart/large blood vessel pathology
- Microangiopathic haemolytic anaemia (e.g. HUS, TTP, DIC)
- Burns
- Infections
- Drugs & chemicals
- Hypersplenism
RBCs may become mechanically damaged from the impact on abnormal surfaces such as metallic heart valves or as they pass through abnormal, intravascular fibrin strands that may be seen in microangiopathic haemolytic anaemias
What are some signs and symptoms of haemolytic anaemia?
Symptoms
- Fatigue
- Weakness
- Paraesthesia
- Dyspnoea
- Gastrointestinal symptoms (e.g. nausea, dyspepsia)
- Weight loss
Signs
- Atrophic glossitis
- Pallor
- Fever
- Splenomegaly
- Evidence of underlying disease
Haemolysis
- Jaundice
- Abdominal pain (e.g. gallstones)
- Dark urine (e.g. haemoglobinuria secondary to intravascular haemolysis)
Underlying aetiology
- Neurological signs (e.g. TTP)
- Splenomegaly
What tests do you need to do for a haemolysis screen and what will they show if there is hameolysis?
- FBC inc Reticulocyte count
- Blood film: spherocytes which is prominent feature in AIHA
- Direct Coombs Test
- Bilirubin
- LDH
- Haptoglobin
What is the MCV in haemolytic anaemia?
Normocytic
What might you see on blood film with haemolytic anaemia?
- Spherocytes (e.g. hereditary spherocytosis)
- Schistocytes (e.g. microangiopathic haemolytic anaemia)
- Sickle cells (e.g. sickle cell disease)
What is the pathophysiology of immune mediated haemolytic anaemia?
Binding of antibodies (allo or auto) to erythrocyte membrane, which can lead to fixing of complement and phagocytosis by macrophages
- Alloantibodies: antibodies produced by one individual that will react with antigens of another individual of the same species e.g haemolytic transfusion reaction
- Autoantibodies: generated against components of the individuals own tissue, may be seen in AIHA
What is the difference between cold and warm AIHA?
Warm AIHA:
Antibody reaction against erythrocytes at higher temperatures (e.g. > 37°), which then leads to agglutination
May be idiopathic, or associated with immune dysfunction secondary to infection, chronic inflammation or malignancy. (HIV, EBV, SLE, CLL, NHL)
Cold AIHA
Reaction against erythrocytes at lower temperatures (e.g. < 32°), which then leads to agglutination.
May be idiopathic or associated with systemic diseases such as lymphoma, Mycoplasma pneumoniae infection and infectious mononucleosis.
Why can it be difficult to cross match patients with AIHA?
Autoantibody can react with several or all of the red cell antigens resulting in agglutination reactions with the entire panel of red cells
Can make it very difficult, if not, impossible to provide compatible blood. It may be impossible to tell if a patient has an alloantibody as all the tests are positive due to the presence of the pan-reacting autoantibody
How are patients with AIHA crossmatched?
To exclude the presence of alloantibodies (in addition to the known autoantibodies) the autoantibody must be removed from the serum
Done in National Blood Service laboratories so acquiring compatible blood can take a long time
How is AIHA managed?
- Blood transfusions
- Prednisolone (steroids)
- Rituximab (a monoclonal antibody against B cells)
- Splenectomy
How are hereditary spherocytosis and elliptocytosis managed?
- Folate supplementation
- Splenectomy
- Cholecystecomy if gallstones are an issue
What can trigger haemolytic anaemia in the X-Linked recessive disease G6PD deficiency?
- Infections
- Medications: primaquine (antimalarial), ciprofloxacin, sulfonylureas, sulfasalazine
- Broad beans
Usually Heinz bodies on blood film. Diagnosis can be made by doing a G6PD enzyme assay
What are some causes of Microangiopathic Haemolytic Anaemia (MAHA)?
Small blood vessels have structural abnormalities that cause haemolysis of the blood cells travelling through them
What is paroxysmal nocturnal haemoglobinuria?
Mutation of haemopoietic stem cells leading to loss of the proteins on the surface of red blood cells that inhibit the complement cascade. Results in activation of clotting cascade against RBC
Red urine in the morning containing haemoglobin and haemosiderin. They are also predisposed to thrombosis (e.g. DVT, PE and hepatic vein thrombosis) and smooth muscle dystonia (e.g. oesophageal spasm and erectile dysfunction)
What is the significance of a raised reticulocyte count in anaemia?
Bone marrow is responsive to EPO
What are the different pathways in the coagulation cascade?
What tests are done on a clotting screen?
PT/INR (12-13 seconds/0.8-1.2)
Time taken for blood to clot via the extrinsic pathway
Measure of overall clotting factor synthesis or consumption.
This test can be affected by liver disease, DIC, vit K deficiency and warfarin
APTT (35-45 seconds)
Time time taken for blood to clot via the intrinsic pathway
APTT, however, can indicate issues with factors VIII (vWF), IX, and XI
Bleeding time (1-6 minutes for finger prick)
Patelet specific disorders will increase the overall bleeding time
Thrombin time (10-15 seconds)
This is a test of how fast fibrinogen is converted to fibrin by thrombin.
Similar to prolonged PT, this can be due to DIC, liver failure, malnutrition, abnormal fibrinolysis and many other conditions.
What are the main conditions leading to an abnormal APTT result?
- Haemophilia A (VIII – X-linked recessive)
- Haemophilia B (IX – X-linked recessive)
- Haemophilia C (XI – autosomal recessive)
- von Willebrands disease (as vWF pairs up with factor VIII)
Note: anti-phospholipid syndrome can cause a high APTT despite being a disorder that causes clots, due to it inactivating the phospholipid used in APTT.
What are the main conditions that increase the bleeding time?
- von Willebrand’s disease (vWF deficiency – autosomal dominant)
- TTP/ITP/HUS/DIC
- Thrombocytopaenia
- Bernard Soulier syndrome
What are some additional tests that can help you to interpret abnormalities on a clotting screen?
- FBC for platelet levels
- LFTs for general liver function
- Albumin
- D-Dimer
- Levels of specific factors
- Antibodies
- Thrombophillia screens
- ADAMTS13 (for TTP)
How can you tell the difference between DIC and ITP/TTP/HUS on a coagulation screen?
What should you never give to patients with ITP/TTP/HUS?
Platelets
What do anticoagulants and antiplatelets do to a clotting screen?
- Anticoagulants: increase PT/INR and APTT
- Antiplatelets: increase bleeding time but normal PT/INR and APTT
What do the following conditions do to a clotting screen?
What are some cause of a high INR?
How do you manage a high INR?
If concern regarding head injury and intracranial haemorrhage, consider CT head
Major bleeding
- Stop anticoagulants
- Administer IV vitamin K
- Administer FFP or prothrombin complex
Minor bleeding
- Stop anticoagulants
- Administer IV vitamin K
- Repeat INR after 24 hours, may need further vitamin K
No bleeding with INR > 8
- Stop anticoagulants
- Administer IV or oral vitamin K
- Repeat INR after 24 hours
No bleeding with INR > 5
- Withhold 1-2 doses of anticoagulant
- Review maintenance dose of anticoagulant
What questions should you ask a patient with a high INR and what should you look for on examination/basic investigations?
History
- Dosing history of anticoagulant/compliance
- Concurrent illness
- Change in medications
- Change in diet/lifestyle (including alcohol and tobacco use)
- History of any falls/injuries
- History of blood loss
- Haemoptysis
- Haematemesis
- Melaena
- Bleeding from the gums
Bloods
- FBC to check for concurrent anaemia, signs of infection
- Clotting screen to check for other clotting abnormalities
Examination
- Evidence of bleeding
- Overt blood loss
- Bruising
What are the inherited and acquired risk factors for VTE?
Hormone therapy with oestrogen
What are some thrombophillias that predispose to VTE?
What is the Well’s score for DVT and how do you manage it depending on the score?
How are VTEs treated and how long for?
Treatment dose apixaban or rivaroxaban
- DOACs: suitable for most patients, including patients with cancer
- Warfarin: vitamin K antagonist, first-line in patients with antiphospholipid syndrome (who also require initial concurrent treatment with LMWH)
- Low molecular weight heparin (LMWH): first-line in pregnancy
In patients with an unprovoked DVT, what differentials should you be considering?
- Thrombophilia testing: Offered if coming off anticoagulation
- Cancer: especially breast and testicular
What is the mechanism of action of the following DOACs?
What is the mechanism of action of LMWH and unfractionated heparin and when would you use one over the other?
What is Heparin-induced thrombocytopaenia (HIT)?
- Antibodies form against complexes of platelet factor 4 (PF4) and heparin
- Develops 5-10 days of treatment
- Low platelets but prothrombotic condition
- 50% reduction in platelets, thrombosis and skin allergy
How do you reverse heparin overdose?
Protamine Sulphate
Only partially works in LMWH, fully works in UFH
What monitoring is done for
- DOACs
- Warfarin
- UFH
- LMWH
DOACs: Annually do FBC, U+Es, serum creatinine
Warfarin: INR
UFH: APTT
LMWH: Anti-Factor Xa not not needed routinely
What is the most common complication of a DVT?
Post-thrombotic syndrome
Chronic swelling, pain and skin changes from venous stasis secondary to chronic venous hypertension
Can lead to ulcers and gangrene
What is Von Willebrand Disease and how does it present?
- Most common inherited haemophilia
- Autosomal dominant
Presentation
Unusually easy, prolonged or heavy bleeding:
- Bleeding gums with brushing
- Nose bleeds
- Heavy menstrual bleeding
- Heavy bleeding during surgical operations
- Family history
How is Von Willebrand disease diagnosed and managed?
Diagnosis
History of abnormal bleeding, family history, bleeding assessment tools and laboratory investigations
Management
Only need to manage if bleeding or prophylaxis before surgery
- Desmopressin can be used to stimulates the release of VWF
- VWF can be infused
- Factor VIII is often infused along with plasma-derived VWF
Haemophilia A (Factor 8 deficiency) and Haemophillia B (Factor 9 deficiency) are both X-Linked recessive. How do they tend to present?
Spontaneous haemorrhage without trauma or excessive bleeding in response to minor trauma
- Intracranial haemorraghe
- Haematomas
- Cord bleeding
- Haemarthrosis
- Gum bleeding
- Gastrointestinal tract bleeding
- Urinary tract causing haematuria
- Retroperitoneal space
How is Haemophillia diagnosed and managed?
Diagnosis
- Bleeding scores
- Coagulation factor assays
- Genetic testing
Management
- Infusions of the affected factor (VIII or IX)
- Desmopressin to stimulate the release of von Willebrand Factor
- Antifibrinolytics such as tranexamic acid
What are some causes of thrombocytopenia?
Either problem with production or an over destruction
Severe
- ITP
- DIC
- TTP
- Haematological malignancy
Moderate
- Heparin induced thrombocytopenia (HIT)
- Drug-induced (e.g. quinine, diuretics, sulphonamides, aspirin, thiazides)
- Alcohol
- Liver disease
- Hypersplenism
- Viral infection (EBV, HIV, hepatitis)
- Pregnancy
- SLE/antiphospholipid syndrome
- Vitamin B12 deficiency
How may thrombocytopenia present?
- Asymptomatic and found incidentally
- Platelet counts <50 x 109/L will result in easy or spontaneous bruising and prolonged bleeding times. They may present with nosebleeds, bleeding gums, heavy periods, easy bruising or blood in the urine or stools.
- Platelet counts < 10 x 109/L are high risk for spontaneous bleeding e.g intracranial haemorraghe or GI bleeding
What is ITP, what is it cause by and how will it present?
- May be detected incidentally following routine bloods
- Petichae, purpura
- Bleeding (e.g. epistaxis)
What is the difference between ITP in children and adults?
Children: transient following viral infection
Adults: chronic relapsing remitting disease
What investigations should you do to diagnose ITP?
- FBC
- Blood film
- Bone marrow only required if atypical
- Further tests to exclude other differential diagnoses (e.g. aplastic anaemia, leukaemia, thrombocytic thrombocytopenic purpura)
How is ITP managed?
- Oral prednisolone first line
- IVIG is quicker way of raising platelets than steroids so use if actively bleeding
- Rituximab (a monoclonal antibody against B cells)
- Splenectomy rarely
What is some supportive care for ITP patients?
- Inform when to seek help e.g malena, persistent headache
- Suppress menstruation
- Control blood pressure
What is Thrombotic Thrombocytopenic Purpura and the pathophysiology of this?
Abnormally large and sticky multimers of von Willebrand’s factor cause platelets to clump within vessels so blood clots throughout small vessels cause thrombocytopenia and bleeding under the skin
Blood clots break down and cause a haemolytic anaemia
Deficiency of ADAMTS13 (a metalloprotease enzyme) which breakdowns large multimers of von Willebrand’s factor
Overlaps with haemolytic uraemic syndrome (HUS)
What are some causes of TTP?
- Post-infection e.g. urinary, gastrointestinal
- Pregnancy
- Drugs: ciclosporin, oral contraceptive pill, penicillin, clopidogrel, aciclovir
- Tumours
- SLE
- HIV
How does TTP present and why does it need to be treated urgently?
Fatal if not managed as causes blockage of small vessels to heart, brain, kidneys etc
- Fever
- Fluctuating neuro signs (microemboli)
- Microangiopathic haemolytic anaemia
- Thrombocytopenia
- Renal failure
How is TTP managed?
Plasma exchange, steroids and rituximab
What are the functions of the spleen?
- Immunity against encapsulated bacteria
- Controls level of WBC, RBC, Platelets
- Filters blood and removes any old or damaged red blood cells
What are some causes of hyposplenism?
- Sickle cell
- Coeliacs
- Lymphoma
- Bone marrow transplant
What will blood results show in hypersplenism?
- Increased platelet count
- Lymphocytosis
- Monocytosis
- Howell Jolly Bodies on peripheral blood smear
How is hyposplenism managed?
- Pneumococcal, Meningitis and Flu vaccine
- Malaria prophylaxis when travelling
- Prophylactic Penicillin V in first few years and then if high risk after that
- Splenectomy card
What are some indications for a splenectomy?
- Trauma
- Spontaneous rupture: e.g in EBV
- Hypersplenism
- Neoplasia: lymphoma or leukaemic infiltration.
- With other viscera: total gastrectomy, distal pancreatectomy.
- Other indications: splenic cysts, hydatid cysts, splenic abscesses
What are some complications with splenectomy?
- OPSI
- Thrombocytosis (7-10 days post op)
What is some post splenectomy prophylaxis given?
What are some causes of splenomegaly?
- Malaria
- Leukaemia/Lymphoma
- EBV
- RA
- Cirrhosis
- Haemolytic anaemia
What is benign polyclonal hypergammaglobulinaemia?
(image is important)
- Usually asymptomatic
- It is an immune response to infections or autoimmune disease or cancers
- Cannot be myeloma as it is not monoclonal
What are some causes of benign polyclonal hypergammaglobulinaemia?
No M spike like in multiple myeloma
What is amyloidosis and the pathophysiology of this?
- Group of conditions caused by the deposition of extracellular insoluble fibrins in organs and blood vessels.
- Primary: deposition of monoclonal light chains in tissues. Happens spontaneously or in association with Multiple Myeloma or Waldenstrom’s macroglobulinaemia
- Secondary: underlying disorders
What is an amyloid fibril?
Insoluble protein fibres that are resistant to degradation
Beta pleated sheets
AL amyloidosis is seen in multiple myeloma. What are some of the clinical features of this?
- Heart failure: shortness of breath, orthopnoea, oedema
- Arrhythmias: palpitations
- Pleural effusions
- Asymptomatic proteinuria: frothy urine
- Nephrotic syndrome
- CKD
- Hepatomegaly
- Dysmotility of gut
- Peripheral neuropathy
- Autonomic neuropathy
- Abnormal clotting
How is amyloidosis diagnosed?
Tissue biopsy from abdominal fat pad or rectum
Congo red staining, which leads to apple-green birefringence under polarised light
What is a paraproteinaemia?
Build-up of monoclonal protein (either the full antibody or antibody fragments) in the serum or urine
Classified into pre-malignant (MGUS) and malignant types (MM, WM)
What are some risk factors for DIC?
- Major trauma or burns
- Multiple-organ failure
- Severe sepsis or infection.
- Severe obstetric complications
- Solid tumours or haematological malignancies
What do you find on blood tests with DIC?
- Thrombocytopenia
- Increased prothrombin time
- Increased fibrin degradation products (such as D-dimer)
- Decreased fibrinogen
What are some side effects of Methotrexate? (Methotrexate Monday, Folate Friday)
- Cytopenia - Monitor FBC and advise patients to report suspected infections and bruising
- Hepatotoxicity - Monitor LFTs, discontinue if they rise to more than 3x
- Renal impairment - Monitor renal function.
- Pulmonary fibrosis - Take baseline CXR. Advise patients to report respiratory symptoms eg. dyspnoea/dry cough.
- Teratogenicity - Advise patients to use contraception while taking and for 3 months after use.
What are side effects of corticosteroids?
- Adrenal suppression of cortisol
- Immunosupression so live vaccines CI
- Reactivation of latent infections (TB / Hepatitis B/C / Herpes viruses)
- Cushingoid appearance with central obesity, buffalo hump, moon face
- Acne
- Thinned skin with striae
- Hyperglycaemia.
- Cushing’s disease - Hypokalaemic hypertension
- Growth retardation in children
- Muscle wasting
- Mood swings
- Steroid psychosis
- Dyspepsia
- Glaucoma
- Cataracts
- Raised white cell count
How is adrenal suppression with long term steroids avoided?
- If they are taken for less than 3 weeks steroids can be safely stopped abruptly.
- If taken for longer than this, the steroids must be tapered down slowly.
- ‘Sick day rules’ - if acutely unwell double the usual dose of prednisolone or supplement IV hydrocortisone (usually 100mg 6-hourly) if unable to tolerate oral medication.
- If nil-by-mouth (or vomiting prednisolone before it can be absorbed), convert the increased daily dose of prednisolone to the equivalent IV hydrocortisone.
In MHP what is an important investigation to do to check platelets?
Thromboelastography (TEG)
When does Graft Vs Host disease present?
1-2 weeks after transfusion
May present with fever, skin rash, GI issues, pancytopenia
Uncommon now as blood is leucodepleted, only issue in immunosuppressed patients
Can be seen in first degree relative blood transfusions if blood not irradiated
How can you tell the difference between TACO and TRALI?
TACO: raised BP, No temp
TRALI: low BP, temp
LOOK AT CXR
